Genetic Variant ATXN2:p.Arg130Arg (chr12-111599125-G-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The ENST00000550104.5(ATXN2):c.390C>G(p.Arg130Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R130R) has been classified as Benign.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATXN2
ENST00000550104.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.132

Publications

0 publications found

Variant links:

Genes affected

ATXN2 (HGNC:10555): (ataxin 2) This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ATXN2 links:

ATXN2-AS (HGNC:51838): (ATXN2 antisense RNA)

ATXN2-AS links:

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new If you want to explore the variant's impact on the transcript ENST00000550104.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP7

Synonymous conserved (PhyloP=-0.132 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000550104.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATXN2	NM_001372574.1	MANE Select	c.-91C>G	5_prime_UTR	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
ATXN2	NM_002973.4		c.-91C>G	5_prime_UTR	Exon 1 of 25	NP_002964.4	V9GY86
ATXN2	NM_001310121.1		c.-65+450C>G	intron	N/A	NP_001297050.1	Q2M2R5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN2	ENST00000550104.5	TSL:1	c.390C>G	p.Arg130Arg	synonymous	Exon 1 of 25	ENSP00000446576.2	Q99700-1
ATXN2	ENST00000673436.1	MANE Select	c.-91C>G		5_prime_UTR	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
ATXN2	ENST00000608853.5	TSL:1	c.-91C>G		5_prime_UTR	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1095716

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

522812

African (AFR)

AF:

0.00

AC:

AN:

22326

American (AMR)

AF:

0.00

AC:

AN:

8210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14178

East Asian (EAS)

AF:

0.00

AC:

AN:

25484

South Asian (SAS)

AF:

0.00

AC:

AN:

24832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2940

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

931950

Other (OTH)

AF:

0.00

AC:

AN:

43734

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

-0.13

PromoterAI

-0.095

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over